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Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy Publisher Pubmed



Wong HH1 ; Seet SH1 ; Maier M2 ; Gurel A3 ; Traspas RM2 ; Lee C1, 4 ; Zhang S3 ; Talim B5 ; Loh AYT1 ; Chia CY2 ; Teoh TS2 ; Sng D2 ; Rensvold J6, 7 ; Unal S8, 9 Show All Authors
Authors
  1. Wong HH1
  2. Seet SH1
  3. Maier M2
  4. Gurel A3
  5. Traspas RM2
  6. Lee C1, 4
  7. Zhang S3
  8. Talim B5
  9. Loh AYT1
  10. Chia CY2
  11. Teoh TS2
  12. Sng D2
  13. Rensvold J6, 7
  14. Unal S8, 9
  15. Shishkova E10, 11
  16. Cepni E12
  17. Nathan FM13
  18. Sirota FL14
  19. Liang C3
  20. Yarali N15
  21. Simsekkiper PO16
  22. Mitani T17
  23. Ceylaner S18
  24. Armanbilir O15
  25. Mbarek H19
  26. Gumruk F8, 9
  27. Efthymiou S20
  28. Ugurlu Cimen D21
  29. Georgiadou D2
  30. Sotiropoulou K1
  31. Houlden H22
  32. Paul F1
  33. Pehlivan D17, 23, 24
  34. Laine C25, 26
  35. Chai G27, 28
  36. Ali NA2
  37. Choo SC2
  38. Keng SS1
  39. Boisson B25, 26, 29
  40. Yilmaz E21
  41. Xue S1, 30
  42. Coon JJ7, 10, 11, 31
  43. Ly TTN1, 30
  44. Gilani N32
  45. Hasbini D33
  46. Kayserili H21
  47. Zaki MS34
  48. Isfort RJ35
  49. Ordonez N36
  50. Tripolszki K36
  51. Bauer P36
  52. Rezaei N37, 38
  53. Seyedpour S40
  54. Khotaei GT39
  55. Bascom CC35
  56. Maroofian R20
  57. Chaabouni M40
  58. Alsubhi A41, 42
  59. Eyaid W41, 42
  60. Isikay S43
  61. Gleeson JG27, 28
  62. Lupski JR17, 23, 24, 44
  63. Casanova JL25, 26, 29, 45, 46
  64. Pagliarini DJ6, 7, 10, 47, 48, 49
  65. Akarsu NA3
  66. Maurerstroh S14
  67. Cetinkaya A3
  68. Bertoliavella A36
  69. Mathuru AS1, 13, 50
  70. Ho L1, 4
  71. Bard FA1
  72. Reversade B1, 2, 21, 51

Source: American Journal of Human Genetics Published:2021


Abstract

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems. © 2021 American Society of Human Genetics